' United States Patent [191

Badorc et al.
[54] DEXTRO-ROTATORY ENANTIOMER OF
METHYL ALPHA-5 (4,5,6,7-TETRAHYDRO
(3,2-C) THIENO PYRIDYL)
(Z-CHLOROPHENYD-ACETATE AND THE
PHARMACEUTICAL COMPOSITIONS
CONTAINING IT

[75] Inventors: Alain Badorc, Roquettes; Daniel

Frhel, Toulouse, both of France

[73] Assignee: Sano?, France

[21] Appl. No.: 155,550
[22] Filed:

[30]

Patent Number:

4,847,265

[45]

Date of Patent:

Jul. 11, 1989

OTHER PUBLICATIONS
Fieser et al., Advanced Org. Chem-Reinhold Publish

ing Co., N.Y., (1961), pp. 85-88.

Primary Examiner-Mary C. Lee
Assistant Examiner-Bernard I. Dentz

Attorney, Agent, or Firm-Wegner & Bretschneider

[57]

ABSTRACT

The present invention relates to the dextro-rotatory

enantiomer of Formula

Feb. 12, 1988

COOCH3

Foreign Application Priority Data

Feb. 17, 1987 [FR]

Nov. 27, 1987 [FR]

[51]
[52]
[58]

[11]

France .............................. .. 87 02025

France .............................. .. 87 16516

Int. cu ................... .. A61K 31/44; CO7D 495/04

U.S.C1. ............................ .. 514/301; 546/114
Field of Search ....................... .. 546/114; 514/301

[56]

References Cited
U.S. PATENT DOCUMENTS
4,529,596

7/1985

Aubert et al. ..................... .. 546/115

U
5

Cl

and its pharmaceutically acceptable salts with platelet

aggregation inhibiting activity.

The invention also relates to a process for the prepara

tion of this compound starting from the racemate and

the pharmaceutical compositions containing it.

FOREIGN PATENT DOCUMENTS

0099802

7/1983

European Pat. Off. .

7 Claims, N0 Drawings

4,847,265

The present invention thus relates more particularly

to the hydrogen sulfate, the taurocholate and the hydro
bromide of the dextro-rotatory enantiomer of methyl

DEXTRO-ROTATORY ENANTIOMER OF

METHYL ALPHA-5 (4,5,6,7-TETRAHYDRO (3,2-C)

alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl) (2
chlorophenyl)-acetate.

THIENO PYRIDYL)
(2-CHLOROPHENYD-ACETATE AND THE
PHARMACEUTICAL COMPOSITIONS
CONTAINING IT

These salts are prepared in a standard manner by the

action of the corresponding acid on the base in solution

in a solvent from which they precipitate spontaneously

The present invention relates to the dextro-rotatory

or after addition of a non-solvent of the salt.

enantiomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2

c)thieno pyridyl) (2-chlorophenyl)-acetate, a process
for its preparation and pharmaceutical compositions
containing it.

The dextro-rotatory isomer of methyl alpha-5(4,5,6,7

tetrahydro(3,2-c)thieno pyridyl) (2-chlorophenyl)-ace

tate can be prepared by forming the salt of the racemic

compound with an optically active acid in a solvent,
The compound of the invention corresponds to the
repeated recrystallizations of the salt until a product of
15 constant optical rotatory power is obtained, followed
following formula (I):
by the liberation of the dextro-rotatory isomer from its
salts by a base; if required, a salt is formed between the
COOCH;
(I)
dextro-rotatory isomer and a pharmaceutically accept
N

able acid.
20

The optically active acid may advantageously be

levo-rotatory camphor-lO-sulfonic acid.

Cl

One and the same solvent may be used for salt forma

in which the C" is an asymmetric carbon atom. In fact,

tion and recrystallization: acetone is ideally suited in

this formula represents both the dextro-rotatory mole 25

this case.

cule claimed as well as its levo-rotatory enantiomer.

The racemic mixture corresponding to this formula was

Formula (I11) is allowed to react in an inert solvent with

The chiral, levo-rotatory camphor- lO-sulfonic acid of

the racemic mixture of Formula (I) according to the

described in the French patent application published

under the No. 2 530 247. Hereafter the dextro-rotatory
enantiomer claimed according to the invention will be

following reaction scheme:

designated by Id and the levo-rotatory enantiomer by I1.

COOCH3

It is known that the optical rotatory power of a com

pound depends on the solvent in which it is measured

and on its concentration in this solvent. The optical

rotatory power of the dextro-rotatory isomer according 35

Cl

to the invention is positive in methanolic solution.

In an unexpected manner only the dextro-rotatory

(1)

enantiomer Id exhibits a platelet aggregation inhibiting

activity, the levo-rotatory enantiomer I1 being inactive.
Moreover, the inactive levo-rotatory enantiomer I1 is

H3C

CH3

the less well tolerated of the two enantiomers.

The invention also relates to the addition salts of the

compounds of formula (14) with pharmaceutically ac

ceptable mineral or organic acids.
The compound (Id) is an oil whereas its hydrochlo

iHZ
SO3H

45

ride exists as a white powder. The oily products are

usually dif?cult to purify and it is preferable to use for

\0

(III)

the preparation of pharmaceutical compositions crystal

line products which can usually be puri?ed by recrys
tallization.

I?N+

However, it has been observed in the present case

that some of the salts of compound (14) usually precipi

tate in an amorphous form and/or that they are hygro
scopic, a property which makes them dif?cult to handle
on an industrial scale. Thus, the salts of carboxylic acid 55

and sulfonic acids classically used in pharmacy have

been prepared, acids such as acetic, benzoic, fumaric,

maleic, citric, tartaric, gentisic, methane-sulfonic,

ethanesulfonic, benzenesulfonic and laurylsulfonic acids

Illa

COOCH3

Cl

CH3
HJC

503
CH2
=0

as well as the salts of dobesilic acid (m.p. =70 C.) and

para-toluenesulfonic acid (m.p.=5l C.), the puri?ca

tion of which proved to be dif?cult.
Among the mineral and organic acid salts of the dex

Salt formation may be carried out in solvents such as

tro-rotatory isomer of the compound of Formula (14)

alcohols, ketones, dimethylformamide. The salt precipi

salts have been found which crystallize easily, are not 65 tates spontaneously or is isolated by salting out or evap
oration of the solvent. A mixture of two diastereoiso
hygroscopic and are sufficiently water-soluble as to
make their use as active medicinal principles particu
mers of Formula (IIIa) is formed. By repeated recrystal

larly advantageous.

lizations from a solvent such as acetone the precipitate

4,847,265

is enriched in the salt of the dextro-rotatory isomer of

compound (I). After each recrystallization the optical

CH3
HsC

rotatory power [(111720 of the precipitate is measured at

20 C. in methanol at a concentration varying between LII
1.5 and 2 g/ 100 ml. When the [1111320 stops increasing the

CH3
CH2SO3-NH4EB %

H30

SIO3H
CH2

=O

=O

base of Formula (ID) is liberated from the salt (IIIa) by

the action of a base such as sodium or potassium hydro
gen carbonate in aqueous media at temperatures vary

(V)

ing between 5 C. and 20 C. Evaporation of the ?ltrate

of the ?rst recrystallization IV after the crystals of the
precipitated salt (IIIa) have been ?ltered off, gives a
mixture enriched in the salt of (I1) enantiomer. The
basi?cation of this mixture of diastereoisomeric salts

An aqueous solution of the ammonium salt (V) is chro

matographed on an Amberlite IRN-77 resin. After ly
ophilization of the eluate camphor-lO-sulfonic acid of
Formula (I11) is recovered.
The entire sequence of the process is shown schemati

cally below:

with a weak base such as sodium or potassium hydrogen

carbonate in aqueous solution at temperatures varying

(I) + (111)

between 5 C. and 20 C. leads to a mixture of the two

enantiomers (14) plus (I1) enriched in the levo-rotatory

enantiomer (I1).

acetone

make

This mixture (Id)+(I1) enriched in enantiomer (I1) is

allowed to react with dextro-rotatory camphor-lO-sul 25

|---".-'"'--1 alkaline ; (Id) + (I!)

on) + Li?fPlLQYb aqueous
(II) in excess
NaHCO3

recrystallisation

fonic acid which will be designated as (11.1) in a solvent

acetone

according to the following reaction scheme:

CH3
Hsc

+ (H4)

acetone

/
30

S0311
CH2

(111)

(111) pure
make alkaline with
aqueous NaHCO3

(1111,)
recrystallisation
acetone

/
=0 %

[E
35

(Li) + (II)
(II) > (L!)
with (1])

(IL!)

in excess

(II) dextro-rotatory)

(1111,) pure

dextro<rotatory
enantiomer

make alkaline with

aqueous Nal-ICO;

COOCH3

levo-rotatory
enantiomer

I
N+

Each of the pure enantiomers (Id) and (1;) may be

5

111,,

Cl

CH;
H3C

5'03
CH2
=O

The crystalline mixture of diastereoisomeric salts (IIIb)

obtained is recrystallized from acetone until the optical
rotatory power [111020 of the precipitate remains con
stant. As previously mentioned the optical rotatory
power [0.1020 of the diastereoisomeric salt (IIIb) is de
termined after each recrystallization.
The liberation of the stereoisomeric (I1) from its salt
is carried out in a standard manner, like that for com

pound (Id). Levo-rotatory comphor-lO-sulfonic acid

converted into a salt by means of the standard methods:

for example, the hydrochlorides are prepared by the

addition of a solution of hydrogen chloride gas in di
ethyl ether to a solution of (14) or (I1) in diethyl ether.

DETERMINATION OF THE ENANTIOMERIC

PURITY OF THE DEXTRO-ROTATORY (14) AND
LEVO-ROTATORY (I1) ENANTIOMERS
Two methods have been used:
proton NMR spectroscopy with the addition of a
chiral rare earth

high pressure liquid chromatography using a chiral

stationary phase.
(a) Proton NMR spectroscopy with the addition of a
chiral rare earth The enantiomeric purity (optical pu
rity) was determined by 1H 60 MHz NMR spectros
copy in the presence of a rare earth chiral complex
according to the method described by G. M. WHITE

SIDES et al. (J. Am. Chem. Soc. 19747 96, 1038).

In the racemic product (I), the hydrogen attached to

monium camphor- l0-sulfonate of Formula (V) accord

the asymmetric centre in the a. position to the ester

function appears as a singlet (chemical shift 8:4.87
ppm in CDC13 as solvent. The addition of the rare earth

ing to the reaction scheme:

complex Eu(tfc)3 [tris S-(tri?uoromethyl hydroxyme~

(111) may be obtained from commercially available am

4,847,265

White crystals, m.p.= 198

thy1ene)-d-camphorato europium (111)] to the probe

(c=2.075 g/100 ml water).

(b) Camphor-lO-sulfonic acid salt of methyl alpha

containing a solution of the racemate (I) in CDC13 leads

to the resolution of the initial singlet into two, well

5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl) (2-chloro

separated singlets corresponding to the proton of each

of the two enantiomers (Id) and (11). When the molar
ratio of rare earth complex/compound (I)=0.4, the
separation between the two singlets is about 6 Hz.
With each of the two enantiomers prepared, (Id) and

tate are dissolved in 150 ml of acetone. 9.95 g (0.0397

(11), the same procedure was used as for the racemate

mole) of levo-rotat camphor-lO-sulfonic acid monohy

(I). The smaller chemical shift corresponds to the pro

ton of the dextro-rotatory enantiomer (Id) and the
larger chemical shift to the levo-rotatory enantiomer

drate are added. The clear solution is left to stand at

room temperature. After 48 hours some crystals have
formed. The reaction mixture is concentrated to 50 ml
and left to stand at room temperature for 24 hours. The

phenyl)-acetate (SR 25990 B).

32 g (0.0994 mole) of racemic methyl alpha-5(4,5,6,7

tetrahydro(3,2-c)thieno pyridyl) (2-chlorophenyl)-ace

(11)

crystals obtained are filtered off, washed with acetone

and dried (yield: 55% on the basis of the starting race

The precision of the method was determined by com

paring the 1H (60 MHz) NMR spectra obtained with

mate).
and without addition of the rare earth complex for each
White crystals, m.p.= 165 c., [a]D20= +24.67
of the two. enantiomers (Id) and (I 1) in the pure state or
(c= 1.58 g/ 100 ml; methanol).
as mixtures containing increasing quantities of one of
The crystals obtained above are redissolved in the
the enantiomers. It was observed that it was possible to
detect easily more than 5% by weight of one enantio 20 minimum of boiling acetone (50 ml). The crystals ob
tained after cooling are ?ltered off, washed with ace-1
mer in the presence of the other.
tone and dried (yield: 88%).

(b) High pressure liquid chromatography using a

White crystals, m.p.= 165 c., MDZO: +2415

chiral stationary phase The study was conducted with a
(0: 1.68 g/100 ml; methanol).
liquid chromatograph HP-1084 using a UV detector at
(c) Dextro-rotatory methyl alpha-5(4,5,6,7-tetrahy
215 nm. The chiral stationary phase was DEAE silica 25

dro(3,2-c)thieno pyridyl) (2-chlorophenyl)-acetate.

(10 microns) onto which was grafted alpha-l acid gly

12 g (0.022 mole) of the pure product obtained in (b)

coprotein (0.4x 100 mm) (ENANTIOPAC R-LKB).

are dissolved in a minimum of water. After cooling to 5

The mobile phase consisted of an aqueous phosphate

C., the aqueous solution obtained is made alkaline with

buffer mixture 8 mM (NaH2PO4/Na2HPO4) containing

0.1M of NaCl, adjusted to pH=7.4, and 15% of isopro

a saturated aqueous solution of sodium hydrogen car

bonate. The alkaline aqueous phase is extracted with

panol (v/v). The flow rate was ?xed at 0.3 ml/minute

and the temperature of the column was maintained at

dichloromethane. The organic extracts are dried over

anhydrous sodium sulfate. On evaporation of the sol

vent a colorless oil is obtained (quantitative yield). Oil,

18-20 C. Under these conditions, the dextro-rotatory

enantiomer (Id) has a retention time of 45 minutes and

the levo-rotatory enantiomer (I1) has a retention time of 35 [a]D2= +51.52 (c= 1.61 g/l00 ml; methanol).

(d) The hydrochloride of methyl alpha-5(4,5,6,7-tet

35 minutes.

rahydro(3,2-c)thieno pyridyl) (2-chlorophenyl)-acetate

The precision of the determination of the optical

(dextro-rotatory) (SR 25990 A).

7 g (0.0228 mole) of dextro-rotatory methyl alpha

purity of the two enantiomers was estimated by

chromatographing each of the two enantiomers (Id) and
(11) prepared either alone or as a mixture containing

5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl) (2-chloro

phenyl)-acetate are dissolved in 100 ml of diethyl ether.
30 ml of a solution of 1N HCl in diethyl ether are added
and the crystals obtained are ?ltered off. The crystals
are washed with diethyl ether and dried (yield: 94%).

increasing amounts of one of the enantiomers. It was

observed that it was easy to detect:

2% (weight/weight) of enantiomer (L1) in enantiomer

(I1)
4% (weight/weight) of enantiomer (11) in enantiomer

45

(Id)
Under these conditions it may be concluded that the

alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)

optical purity of the two enantiomers (Id) and (1;) ob

tained according to the examples is at least equal to 96%
for the dextro-rotatory enantiomer (Id) and at least
equal to 98% for the levo-rotatory enantiomer (I1).

800 ml of a saturated aqueous solution of sodium

bicarbonate are added to a suspension of 200 g of SR

25990 B in 800 ml of dichloromethane. After vigorous

shaking, the organic phase is separated, dried over so
dium sulfate and the solvent is removed under reduced
55 pressure. The residue is dissolved in 500 ml of ice-cold

EXAMPLE 1

acetone and 20.7 ml of concentrated sulfuric acid

Salts of dextro-rotary

methyl-alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)
-

(a) levo-rotatory camphor-lO-sulfonic acid

A column of Amberlite IRN-77 resin is prepared and

tested by passing 1N hydrochloric acid through it and

then by washing this column of acidi?ed resin abun
dantly with water. Levo-rotatory ammonium camphor
10-sulfonate is dissolved in a minimum of water and 65

applied to the column of resin previously prepared.

Elution is carried out with water. The eluted fractions

containing the acid are lyophilized.

(2

chlorophenyD-acetate (SR 25990 C).

The following examples are non-restrictive and are

presented to illustrate the present invention.

(2-chlorophenyl)-acetate

White crystals, m.p.=l17 C., [a]D2= +6223

(c= 1.82 g/100 ml; methanol).
(e) The hydrogen sulfate of dextro-rotatory methyl

(93.64%, d= 1.83) are added drop-wise. The precipitate

formed is isolated by ?ltration and washed with 1,000
ml of acetone, then dried in a vacuum oven at 50 C.

139 grams of analytically pure white crystals are thus

obtained with a melting point of 184 C. Empirical

formula:
C16H16ClNO2S.H2SO4 [0.];320: + 55.10

(c= 1.891 g/ 100 ml; methanol).

(f) The hydrobromide of dextro-rotatory methyl al

pha-5(4,5,6,7-tetrahydro(3,2-c)thieno
chlorophenyl)-acetate (SR 25990D).

pyridyl)

(2

150 ml of an aqueous solution of sodium bicarbonate

are added to a suspension of 20 g of SR 25990 B in 200

4,847,265

ml of dichloromethane. The residue obtained after sepa

acetone and dried. White crystals, m.p.= 167 C.,

ration of the organic phase, drying and evaporation of

[a]D20= 24.85 (c: 1.79 g/ 100 ml; methanol).

the solvent is dissolved in 150 ml of diethyl or diisopro

pyl ether, and 4.4 ml of a 48% (wt/v) aqueous solution
of hydrobromic acid are added drop-wise. The precipi

(b) Levo-rotatory methyl alpha-5(4,5,6,7-tetrahy

dro(3,2-c)thieno pyridyl) (2-chlorophenyl)-acetate.

tate formed is isolated. After drying, 14.4 g of crystals

obtained in (a) are dissolved in a minimum of water. The

are obtained with a melting point of 111 C. (yield

aqueous solution obtained is cooled to 5 C. and made

alkaline with a saturated aqueous solution of sodium

11.3 g (0.0204 mole) of the camphor-IO-sulfonate

99%).

hydrogen carbonate. The alkaline aqueous phase is

extracted with dichloromethane. The organic solution
is dried and the solvent is evaporated. A colourless oil is

13.4 g of these crystals are recrystallized from a mix

ture of isopropyl ether (100 ml) and isopropanol (150

ml) to give 10.2 g of analytically pure hydrobromide:

isolated (quantitative yield).

Oil [a]D2= 50.74 (c: 1.58 g/100 ml; methanol).
(0) The hydrochloride of levo-rotatory methyl alpha

m.p.=l40 C.; empirical formula: C16H16ClNO2S.HBr

[a]D2= +5923 (c=2.09 g/ 100 ml; methanol).
(g) The taurocholate of dextro-rotatory methyl al=

pha-5(4,5,6,7-tetrahydro(3,2-c)thieno
chlorophenyl)-acetate (SR 25990E).

pyridyl)

5(4,5,6,7tetrahydro(3,2-c)thieno pyridyl) (2-chloro

(2

phenyl)-acetate (SR 25989 A).

Prepared according to the method described in Ex

The sodium salt of taurocholic acid is chromato

graphed on Amberlite IRN-77 resin by eluting with

water. The fractions obtained are lyophilized.
20
3 g (0.0054 mole) of SR 25990B are treated with a
saturated aqueous solution of sodium bicarbonate and
the mixture is extracted with dichloromethane. The

organic phase is separated, dried over sodium sulfate

(a) Salt of d-camphor-lO-sulfonic acid (SR 25989 B)

After separation of SR 25990 B in Example l-b the
solvent is evaporated from the acetone ?ltrate obtained.
The residue is taken up in water and diethyl ether.
The ethereal phase is decanted. The aqueous phase is
cooled to 5 C. and made alkaline with a saturated aque
ous solution of sodium bicarbonate. The aqueous alka

line phase is extracted with diethyl ether. The ethereal

extracts are pooled and dried over anhydrous sodium

sulfate.
On evaporation of the solvent an oil is obtained
which- is puri?ed by ?ltration through a bed of silica

(eluant: diethyl ether). A colourless oil is recovered

consisting of a mixture of about 65% of the levo-rota
tory enantiomer and 35% of the dextro-rotatory enan

tiomer, proportions determined by means of 1H (60

MHz) NMR spectroscopy after the addition of chiral,

pyridyl)

(2

chlorophenyl)-acetate (SR 25989 C).

saturated aqueous solution of sodium bicarbonate in the

presence of dichloromethane. The organic phase is

separated, dried over sodium sulfate and evaporated to
dryness. The residue is taken up in 300 ml of acetone
and 7.2 ml (0.126 mole) of concentrated sulfuric acid are

added drop-wise. After being stirred the crystals

formed are ?ltered off and washed with acetone. 47.8 g
of white crystals are obtained. m.p.= 182 C.

agreement with theory.

alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)
(2-chlorophenyl)-acetate

(d) The hydrogen sulfate of levo-rotatory methyl

alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno

B obtained are treated as described in (a) above with a

[a]D2+=39.53 (c=1.79l g/100 ml of methanol).

C16H16ClNO2S.Cz6H45NO7S; C, H, N analyses in
EXAMPLE 2

(c: 1.80 g/100 ml; methanol).

70 g (0.126 mole) of the camphor sulfonate SR 25989

and evaporated to dryness. The free base obtained is

taken up in 30 ml of isopropanol; 2.8 g (0.0054 mole) of
taurocholic acid dissolved in 100 ml of isopropanol are
added to this solution. The mixture is stirred overnight
at room temperature, then evaporated to dryness. The
residue solidifed on being triturated with ether. 3.5 g of
beige crystals are obtained. m.p.= 120 C.

Salts of levo-rotatory methyl

ample 1(d). Yield: 94%.

White crystals, m.p.=117

35

Mb: -51.61 (c=2.044 g/ 100 ml; methanol). The

analysis (C,H,N) are in agreement with theory.
PHARMACOLOGICAL STUDY

The platelet aggregation inhibiting activity and the

toxicity of these new compounds were compared to
those of the racemic mixture described in the French
Pat. No. 82.12599 (Publication No. 2 530 247).
A description will now be given of the results of this

study which demonstrates another advantage of the

invention, namely that the salts of the dextro-rotatory
isomer have a better therapeutic index than the salt of

the racemic mixture; in fact, the levo-rotatory isomer

exhibits almost no platelet aggregation inhibiting activ

ity and its toxicity is markedly higher than that of its

dextro-rotatory homologue.
The platelet aggregation inhibiting activities and the
.antithrombotic activities of the compounds were stud
ied in the rat by standard methods.

The activity on the aggregation of plates induced by

ADP or collagen was determined ex-vivo.

The products dissolved in ethanol (200 mg/ml) and

diluted in water containing gum arabic (5%-wt/v) were

administered by the oral route to groups of ?ve female
rare earth complex.
rats of the CD-COBS strain, weighing 250-300 g, in
16.66 g (0.0517 mole) of the mixture thus obtained are
amounts of 10 ml of suspension per kilogram two hours
dissolved in 70 ml of acetone. 7.77 g (0.0310 mole) of 60 before blood samples were taken.
dextro-rotatory camphor-IO-sulfonic acid monohydrate
The blood samples were taken from animals anesthe
are added. The homogeneous mixture is left to stand
tized with diethyl other by puncture of the abdominal
overnight at room temperature. The crystals obtained
aorta and placed over a 3.8% aqueous solution of so
are ?ltered off, washed with acetone and dried (yield:
dium citrate (1 vol/ 9 volumes of blood). The platelet
44% based on the mixture).
65 rich plasma was then isolated by centrifugation at 200 g
The crystals obtained are dissolved in a minimum of
for 10 minutes.

re?uxing acetone (60 ml). The precipitate obtained on

cooling to room temperature is ?ltered off, washed with

Aggregation is induced by the addition of 2 ul of

aggregating solution to 400 p.l of platelet-rich plasma.

4,847,265

10

100. The results shown in Table II demonstrate again

that only the dextro-rotatory isomer is active whereas
the salts have comparable activities.
TABLE II
QUAN

The aggregating solutions used were: a 500 uM aqueous

solution of ADP marketed by Boehringer Mannheim

(?nal concentration 2.5 uM), and a solution of collagen
marketed by Sigma (type 1) at a concentration of 0.25
g/ 100 ml in 3% acetic acid (v/v) (?nal concentration

12.5 ug/ml).
The aggregation of the platelets was monitored as
described in the method by G. V. R. Born in Nature

PRO-

DOSE
TITY
mg/Kg of base ad-

DUCT

194, p. 927 (1967) using a Coultronics aggregometer

R0

Controls

at a temperature of 37 C. and agitation of 900 rpm.

ministered
_

SLOPE

% IN
I-IIBI
TION P"

4.8 +/ 0.3

PCR 4099
(racemate)

4.48
8.97
17.9

3.84
7.69
15.38

3.6 +/ 0.2
2.7 +/ 0.3
1.5 +/- 0.3

25
44
69

0.05
0.01
0.001

sured by a change in optical density. The height of this

SR 25989C

curve is de?ned as the height of aggregation. The per

SR 25990C

20
40
1.25
2.5

15.38
30.76
0.96
1.92

4.3
4.0
4.5
4.1

+/+/
+/
+/

0.2
0.2
0.3
0.2

10
17
6
15

n.s
n.s
n.s
n.s

5
10

3.84
7.69

0.1
0.3
0.1
0.5
0.4
0.29
0.33
0.34
0.42
0.29
0.19
0.22
0.14
0.13

0.001
0.001

3.84
7.69

+/
+/
+/
+/
+/+/
+/
+/
+/
+/
+/+/
+/
+/

52
65

10
20

2.3
1.7
3.5
2.1
1.4
3.97
3.13
2.94
2.19
4.32
3.05
1.24
0.86
0.74

40
60

0.05
0.01

For aggregation with ADP, the aggregometer gener

ates a curve representing a platelet aggregation as mea

centage of aggregation is the relation between the ag

gregation height measured and the height correspond

ing to 100% aggregationX 100. The percentage of inhi
bition is determined by the relation:

Controls
SR 25990E

20 Controls

Control aggregation height

The results obtained for the aggregation with ADP

for the hydrochloride of the racemic mixture (PCR

4099), the hydrogen sulfates of the dextro-rotatory (SR

PCR 4099

2.5

2.14

(racemate)

5
12.5

4.28
10.71

SR 25989.4
SR 25990A

25
2.5
5
12.5
25

22.46
2.25
4.49
11.23
22.46

25990 C) and levo-rotatory (SR 25989 C) isomers on the

one hand, and for PCR 4099 and the hydrochlorides of

the dextro-rotatory (SR 25990 A) and levo-rotatory

screw thread described by Kumada T. et al. in Thromb.

TABLE I

Res 18 p. 189 (1980).

DOSE QUANTITY
mg/Kg
of base

% IN
I-IIBI

administered

TION P

Female rats of the same type as those previously

35 described, in groups of 10 animals, were anesthetized
with diethyl ether and their vena cava was isolated after

% AGGRE
GATION
Controls
PCR 4099
(racemate)
SR 25989C

SR 25990C

Controls
SR 25990E

4.48
8.97
17.9
20
40
1.25
2.5
5
10
10
20

3.84
7.69
15.38
15.38
30.76
0.96
1.92
3.84
7.69
3.84
7.69

42.4
29.8
17.2
11.1
41.0
37.1
39.4
28.4
14.0
8.5
33.8
9.6
4

+/
+/
+/
+/+/
+/
+/
+/
+/
+/
+/
+/
+/

1.5
2.4
2.2
2.3
1.5
1.7
1.3
2.3
1.6
1.6
2.3
3
1.6

abdominal incision.
A metallic screw thread 21 mm long consisting of a
30
59
74
3
13
7
33
67
80

0.01
0.001
0.001
n.s
n.s
n.s
0.01
0.001
0.001

72
88

0.001
0.001

AGGREGA
TION
HEIGHT

Controls
PCR 4099
(racemate)
SR 25989A
SR 25990A

2.5
5
12.5
25
2.5
5
12.5
25

n.s
0.05
0.001
0.001
0.001

also been studied in the test of venous thrombosis on a

as the racemate.

P.O

10
23
69
78
81

The antithrombotic activity of these compounds has

and that the dextro-rotatory isomer is at least as active

PRO-

n.s

0.05
0.01

Student test
n.s. not signi?cant

(SR 25989 A) on the other, are shown in Table I; they

demonstrate that the levo-rotatory isomer is inactive

DUCT

21

26
45

2.14
4.28
10.71
22.46
2.25
4.49
11.23
22.46

103
86
72
32

+/
+/
+/
+/

5
5
8
9

101
67
26
19
11

+/
+/
+/
+/+/

1
7
5
4
1

dentists drill, marketed by Dyna (France) size No. 30,

was introduced into the lumen of this vein just below

the renal bifurcation descending towards the iliac veins,

without damaging the wall; 19 to 20 mm of the length of
45

50

the screw thread are implanted and the remaining 1 mm

' protrudes through the closed stomach into the exterior.

The thrombi formed rapidly and five hours later,

under pentobarbital anesthesia, the abdomen is re
opened and ligatures are placed above and below the
screw thread which is withdrawn after longitudinal
incision of the vein and the isolated thrombus is

weighed.
The results which are presented in Table III show

that the levo-rotatory isomer is inactive in this test, in

17
30
69
2
35
75
82
89

0.05
0.05
0.001
n.s
0.01
0.001
0.001
0.001

contrast to the dextro-rotatory isomer and the race

55

mean of results +/ standard error of the mean (SEM)

"Student test

"'aggregation height in mm: mean +/- SEM (n = 5)

n.s. not signi?cant

For the aggregation with collagen, the percentage of

inhibition is the difference of the slopes of the curves 65
representing the variation of the optical density as a
function of time for the control and the product to be

tested divided by the slope of the control multiplied by

mate.

TABLE III
DOSE

rug/Kg QUANPRODUCT

Controls
PCR 4099
(racemate)
SR 25989C
SR 25990C

P.0
admin.

4.48
8.97
17.9
40
1.25
2.5
5
10
20

TITY
of base

3.84
7.69
15.38
30.76
0.96
1.92
3.84
7.69
15.38

VARIA
WEIGHT of
thrombi

3.9
2.17
1.39
1.00
4.17
3.11
2.29
1.71
1.26
1.20

+/+/
+/
+/+/
+/
+/
+/
+/
+/

0.3
0.24
0.15
0.19
0.42
0.32
0.22
0.24
0.19
0.13

TION
%

44
64
74
7
20
41
56
67
69

0.001
0.001
0.001
n.s
n.s
0.01
0.01
0.01
0.01

4,847,265

11
TABLE III-continued

examples.

DOSE

mg/Kg QUANPRODUCT

Controls
SR 2599015

P.O
admin.

TITY
of base

10
20

3.84
7.69

12

the invention will be given below as non-restrictive

(1) Tablets
Active ingredient: 0.010 g

VARIA
WEIGHT of
thrombi

TION
%

P"

Excipient: lactose, powdered sugar, rice-starch, alginic

3.78 +/- 0.36

1.48 +/ 0.15
1.18 +/ 0.15

60
68

0.001
0.001

(2) Sugar-coated tablets

acid, magnesium stearate

Active ingredient: 0.005 g
Excipient: magnesium stearate, maize starch, gum ara
bic, shellac, white sugar, glucose, white wax, car
nauba wax, paraffin, cochineal.

' = weight of thrombi in mg +/- standard error of the mean

P = UtestofXruskal-Wallis

For the toxicological study, the compounds were

(3) Capsules

administered by the oral route in the form of a suspen

Active ingredient: 0.025 g

Excipient: magnesium stearate, maize starch, lactose.

sion in the same volume of water made up to 10%

(wt/v) with gum arabic to groups of 10 fasted female 15 (4) Injectable solution
rats of the Sprague Dawley strain weighing 120 to 135
Active ingredient: 0.050 g
grams.
The number of dead animals was determined 14 days

after the administration of the compound under study.

The lethal doses thus determined, expressed in weight

isotonic saline q.s.p. 3 ml,

(5) Suppositories
Active ingredient: 0.030 g
20

of the salt administered, are presented in Table IV; these

results show on the one hand that the toxicity of the
racemic mixture is similar to that of the levo-rotatory

Semi-synthetic triglycerides q.s.p. l suppository.

On account of its interesting inhibitory properties
towards platelet aggregation and its interference in the
mechanism of formation of arterial and venous throm

isomer whereas the dextro-rotatory isomer is markedly

boses, the medicine of the invention can be usefully
less toxic, and, on the other hand, that the toxicity de 25 administered in the treatment and prevention of platelet
pends on the nature of the acid used to form the salt.
TABLE IV
D 50

PRODUCTS
PCR 4099

D 10
1318

(racemate)

()
1615

disorders due to extracoporeal blood circuits or the

consequence of complications in atheroma.
We claim:

ABSOLUTE LETHAL

D 90

1. Dextro-rotatory isomer of methyl alpha-5(4,5,6,7

_DOSE

1979

2000

2299

2000

6137

5000

2974

4000

6914

5000

30

tate substantially separated from the levo-rotatory iso

mer and its pharmaceutically acceptable salts.
2. Hydrochloride of the dextro-rotatory isomer of

(1448-1747)

SR 25989 A

1259

SR 25990 A

3055

1702

(1443-1797)
4316

(3569-5705)
SR 25990 C

2257

SR 25990 D

2634

2591

35

methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)

(2-chlorophenyl)-acetate substantially separated from
the levo-rotatory isomer.
3. Hydrogen sulfate of the dextro-rotatory isomer of

(2372-2805)
4268

tetrahydro(3,2-c)thieno pyridyl) (2-chlorophenyl)-ace

methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)

(3581-6012)

(2-chlorophenyl)-acetate substantially separated from

( ) = con?dence interval

the levo-rotatory isomer.

4. Hydrobromide of the dextro-rotatory isomer of

The pharmacological study just presented has dem

onstrated the interesting inhibitory properties towards
platelet aggregation of the compound Id and the ab

methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)

(2-chlorophenyl)-acetate substantially separated from
the levo-rotatory isomer.

sence of any activity of its isomer 11.

The medicine of the invention can be made available 45

5. Taurocholate of the dextro-rotatory isomer of
for oral administration in the form of tablets, sugar=
methyl alpha-5(4,5,6,7tetrahydro(3,2-c)thieno pyridyl)
coated tablets, capsules, drops, granules or a syrup. It
(2-chlorophenyl)-acetate substantially separated from
can also be made available for rectal administration in
the levo-rotatory isomer.
the form of suppositories or for parenteral administra
6. Pharmaceutical composition which comprises an
tion in the form of an injectable solution.
50 effective platelet aggregation inhibiting amount of a
Each unit dose contains advantageously from 0.001 g
compound of claim 1 and a pharmaceutically acceptable
to 0.100 g of the derivative of the invention, and the
carrier.
daily doses to be administered may vary from 0.001 g to
- 7. Composition according to claim 6, comprising unit
0.500 g of active ingredient depending on the age of the
doses containing from 0.001 g to 0.100 g of active ingre
patient and the severity of the disorder to be treated. 55 dient.
*
*
i
i
i
Some pharmaceutical formulations of the medicine of

65

US004847265C1

(12) EX PARTE REEXAMINATION CERTIFICATE (7 57 1st)

United States Patent
(10) Number:
US 4,847,265 C1
Badore et a].
(54)

(45) Certi?cate Issued:

Jun. 29, 2010

Reist et al., Very SloW Chiral Inversion of Clopidogrel in

DEXTRO-ROTARORY ENANTIOMER OF
METHYL ALPHA-5 (4,5,6,7-TETRAHYDRO

Rats: a Pharmacokinetic and Mechanistic Investigation, 28

(3,2-C) THIENO PYRIDYL)

Drug Metab. & Dispos. 1405. [PX 151] English.

(2-CHLOROPHENYL)-ACETATE AND THE

Wilen et al., Strategies In Optical Resolutions, 33 Tetrahe

PHARMACEUTICAL COMPOSITIONS
CONTAINING IT

dron 2725 (1977). [PX 854]English.

(75) Inventors: Alain Badore, Roquettes (FR); Daniel

Frhel, Toulouse (FR)

(73) Assignee: Sano?-Aventis, Paris (FR)

Reexamination Request:
No. 90/009,474, Jun. 1, 2009

Jacques et al., Enantiomers, Racemates and Resolutions,

Chapter 7, John Wiley and Sons, 1981. [DDX 492, DDX

492D, DDX 492E] English.

Eliel, Racemic Modi?cations, Stereochemistry of Carbon
Compounds, Ch. 4, pp. 31486 (1962). [DTX 1930]English.
Vries et al., The Family Approach to Resolution of Race

mates, AngeW. Chem. Intl. Ed. 2349 (1998). [PX 852]

English.
Ohm et al., Effect of Antiplatelet Agents on Outcomes for

Reexamination Certi?cate for:

(30)

Patent No.:
Issued:

4,847,265
Jul. 11, 1989

Appl. No.:

07/155,550

Filed:

Feb. 12, 1988

Foreign Application Priority Data

Feb. 17, 1987

Nov. 27, 1987

(51)

(52)
(58)

(FR) .......................................... .. 87 02025

(FR) .......................................... .. 87 16516

Int. C1.
C07] 41/00
C07D 495/00
C07D 495/04

(2006.01)
(2006.01)
(2006.01)

US. Cl. ...................................... .. 514/301; 546/114

Field of Classi?cation Search ...................... .. None

See application ?le for complete search history.

(56)

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(Continued)
Primary ExamineriEvelyn Huang
(57)

ABSTRACT

The present invention relates to the dextro-rotatory enanti

omer of Formula

12/2002 Horne

coocH3
FOREIGN PATENT DOCUMENTS
CA
EP
FR
FR
FR

1194875
0099802
82 12599
87 02025
8716516

10/1985
7/1983
7/1982
2/1987
ll/l987

OTHER PUBLICATIONS

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US 4,847,265 C1
1

EX PARTE

AS A RESULT OF REEXAMINATION, IT HAS BEEN

REEXAMINATION CERTIFICATE

ISSUED UNDER 35 U.S.C. 307

DETERMINED THATI
The patentability of claims 1-7 is con?rmed.

NO AMENDMENTS HAVE BEEN MADE TO

THE PATENT